1. Field of the Invention
This invention arises in the technology of pharmaceutical dosage forms, and relates in particular to formulations for drugs that benefit from a prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and from an enhanced opportunity for absorption in the stomach and upper GI tract rather than the lower portions of the GI tract.
2. Description of the Prior Art
Many drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous, controlled manner. Drugs delivered in this manner have fewer side effects and produce their therapeutic effect without the need for repeated or frequent dosing. Localization of the drug delivery in the stomach is an advantage for the treatment of local disorders of the stomach such as esophageal reflux disease, for the eradication of ulcer-causing bacteria in the gastric mucosa, and for the treatment of disorders that require sustained antacid action. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited.
In the normal digestive process, the passage of matter through the stomach is delayed by a physiological condition that is variously referred to as the digestive mode, the postprandial mode, or the xe2x80x9cfed mode.xe2x80x9d Between fed modes, the stomach is in the interdigestive or xe2x80x9cfastingxe2x80x9d mode. The difference between the two modes lies in the pattern of gastroduodenal motor activity.
In the fasting mode, the stomach exhibits a cyclic activity called the interdigestive migrating motor complex (IMMC). This activity occurs in four phases:
Phase I, which lasts 45 to 60 minutes, is the most quiescent, with the stomach experiencing few or no contractions.
Phase II is characterized by sweeping contractions occurring in a irregular intermittent pattern and gradually increasing in magnitude.
Phase III consists of intense bursts of peristaltic waves in both the stomach and the small bowel. This lasts for 5 to 15 minutes.
Phase IV is a transition period of decreasing activity which lasts until the next cycle begins.
The total cycle time for all four phases is approximately 90 minutes. The greatest activity occurs in Phase III whose powerful peristaltic waves sweep the swallowed saliva, gastric secretions, food particles, and particulate debris, out of the stomach and into the small intestine and colon. Phase III thus serves as an intestinal housekeeper, preparing the upper tract for the next meal and preventing bacterial overgrowth.
The fed mode is initiated by nutritive materials entering the stomach upon the ingestion of food. Initiation is accompanied by a rapid and profound change in the motor pattern of the upper gastrointestinal (GI) tract, over a period of 30 seconds to one minute. The change is observed almost simultaneously at all sites along the GI tract and occurs before the stomach contents have reached the distal small intestine. Once the fed mode is established, the stomach generates 3-4 continuous and regular contractions per minute, similar to those of the fasting mode but with about half the amplitude. The pylorus is partially open, causing a sieving effect in which liquids and small particles flow continuously from the stomach into the intestine while indigestible particles greater in size than the pyloric opening are retropelled and retained in the stomach. This sieving effect thus causes the stomach to retain particles exceeding about 1 cm in size for approximately 4 to 6 hours.
The particle size required for gastric retention during the fasting mode is substantially larger than the particle size required for gastric retention in the fed mode. Particles large enough to be retained in the fasting mode are too large for practical administration in most patients. Particles of a smaller particle size can be retained in the stomach if they are administered to a patient who is in the fed mode, and this offers a means of prolonging the amount of time that the particles spend in the stomach.
The prior art of dosage forms for gastric retention also teaches that the residence time of drug formulation particles in the stomach can be prolonged by using particles that are small enough to be swallowed comfortably but swell to a larger size upon contact with the gastric fluid in the stomach. With a great enough degree of swelling, particles of this type achieve gastric retention regardless of whether the subject is in the fed mode or the fasting mode. One means of achieving a swellable particle is to disperse the drug in a solid matrix formed of a substance that absorbs the gastric fluid and swells as a result of the absorbed fluid. Disclosures of this type of particle are found in U.S. Pat. No. 5,007,790 (xe2x80x9cSustained-Release Oral Drug Dosage Form;xe2x80x9d Shell, inventor; Apr. 16, 1991), U.S. Pat. No. 5,582,837 (xe2x80x9cAlkyl-Substituted Cellulose-Based Sustained-Release Oral Drug Dosage Forms;xe2x80x9d Shell, inventor: Dec. 10, 1996): U.S. Pat. No. 5,972,389 (xe2x80x9cGastric-Retentive Oral Drug Dosage Forms for the Controlled Release of Sparingly Soluble Drugs and Insoluble Matter;xe2x80x9d Shell et al., inventors; Oct. 26, 1999); and International (PCT) Patent Application WO 98/55107 (xe2x80x9cGastric-Retentive Oral Drug Dosage Forms for Controlled Release of Highly Soluble Drugs;xe2x80x9d Shell et al., inventors; publication date Dec. 10, 1998).
Polymer matrices have also been used to achieve controlled release of the drug over a prolonged period of time. Such sustained or controlled release is achieved either by limiting the rate by which the surrounding gastric fluid can diffuse through the matrix and reach the drug, dissolve the drug and diffuse out again with the dissolved drug, or by using a matrix that slowly erodes, continuously exposing fresh drug to the surrounding fluid. Disclosures of polymer matrices that function by either of these two methods are found in U.S. Patent No. 6,210,710, (xe2x80x9cSustained release polymer blend for pharmaceutical applications,xe2x80x9d Skinner, inventor, Apr. 3, 2001); U.S. Pat. No. 6,217,903, (xe2x80x9cSustained release polymer blend for pharmaceutical applications,xe2x80x9d Skinner, inventor, Apr. 17, 2001); International (PCT) Patent Application WO 97/18814 (Pharmaceutical Formulations,xe2x80x9d MacRae et al., inventors, publication date May 29, 1997); U.S. Pat. No. 5,451,409, (xe2x80x9cSustained release matrix system using hydroxyethyl cellulose and hydroxypropyl cellulose polymer blends,xe2x80x9d Rencher et al., inventors, Sep. 19, 1995); U.S. Patent No. 5,945,125, (xe2x80x9cControlled release tablet,xe2x80x9d Kim, inventor, Aug. 31, 1999); International (PCT) Patent Application WO 96/26718 (xe2x80x9cControlled Release Tablet,xe2x80x9d Kim, inventor: publication date Sep. 6, 1996); U.S. Pat. No. 4,915,952, (xe2x80x9cComposition comprising drug, HPC, HPMC, and PEO,xe2x80x9d Ayer et al., inventors, Apr. 10, 1990); U.S. Pat. No. 5,328,942, (xe2x80x9cSeed film compositions,xe2x80x9d Akhtar et al., inventors, Jul. 12, 1994); U.S. Pat. No. 5,783,212, (xe2x80x9cControlled release drug delivery system,xe2x80x9d Fassihi et al., inventors, Jul. 21, 1998); U.S. Pat. No. 6,120,803, (xe2x80x9cProlonged release active agent dosage form for gastric retention,xe2x80x9d Wong et al., inventors, Sep. 19, 2000); U.S. Pat. No. 6,090,411, (xe2x80x9cMonolithic tablet for controlled drug release,xe2x80x9d Pillay et al., inventors, Jul. 18, 2000).
The goals of gastric retention and controlled release are not always compatible. Poly(ethylene oxide) is a matrix material that possesses both swelling and controlled release properties, but at the amounts needed for high drug dosage, and particularly the amounts needed for sufficient swelling to achieve gastric retention, the use of poly(ethylene oxide) raises regulatory concerns, since the United States Food and Drug Administration lists poly(ethylene oxide) as a substance with undefined toxicology considerations when used at sufficiently high doses on a long-term basis. Other matrix materials swell but also offer the benefit of a more even and generally faster erosion in the gastric environment so that the dosage forms can clear the GI tract more predictably after a few hours of drug release. One such material is hydroxypropyl methylcellulose, which swells but not to the same degree as poly(ethylene oxide). Hydroxypropyl methylcellulose is not considered a toxicology risk at any level by the FDA. A disadvantage of matrices that erode more readily however is that they cause a high initial burst of drug release and a lower degree of control over the drug release rate over the initial course of the drug release.
It has now been discovered that the use of poly(ethylene oxide) and hydroxypropyl methylcellulose in combination as a matrix for a swellable, sustained-release tablet provides unexpectedly beneficial performance, avoiding or substantially reducing the problems enumerated above and offering improved control and reliability while retaining both the ability to swell for gastric retention and to control drug release. The swelling behavior of poly(ethylene oxide) is retained but balanced against the erosion behavior of hydroxypropyl methylcellulose which modulates the extent and progress of swelling. In certain preferred embodiments of the invention, despite the relatively low level of poly(ethylene oxide), the tablet increases to about 120% of its original weight within the first 30 minutes of contact with gastric fluid and continues to increase in size, reaching at least about 90% of its maximum weight or size within 8 hours and remaining in a swollen state for sufficient time to provide gastric retention. The competing yet complementary actions of swelling and erosion also provide the tablet with greater mechanical integrity so that it disintegrates more slowly and more evenly than tablets with poly(ethylene oxide) as the sole or primary matrix material. By offering a more reproducible erosion rate, the combined-polymer matrix tablet provides greater reproducibility in the drug release rate and transit time through the GI tract while still retaining the swelling behavior that results in gastric retention. A particular benefit of the combined-polymer matrices of this invention is that they provide a tablet with the swelling behavior of poly(ethylene oxide) while maintaining the level of poly(ethylene oxide) below any levels that encounter regulatory obstacles that have been established in view of certain recognized or perceived toxicological effects of poly(ethylene oxide).
The combined-polymer matrices of the present invention offer benefits to drugs ranging from highly soluble drugs whose delivery from the matrix occurs primarily by diffusion out of the matrix after being dissolved by the gastric fluid, to sparingly soluble drugs whose delivery from the matrix occurs primarily by erosion of the matrix. For the highly soluble drugs, the poly(ethylene oxide) component of the matrix limits the initial release of the drug and imparts gastric retention through swelling, while the hydroxypropyl methylcellulose component lowers the amount of polyethylene oxide required while still allowing the swelling to occur. For the sparingly soluble drugs, the hydroxypropylmethyl cellulose component prevents premature release of the drugs by retarding the erosion rate of the poly(ethylene oxide) while the poly(ethylene oxide) provides superior gastric retention. For both high and low solubility drugs, therefore, and for drugs of intermediate solubilities as well, the two polymers function in a complementary manner, benefiting in terms of gastric retention and sustained drug release.
These and other features, advantages, applications and embodiments of the invention are described in more detail below.